Human Molecular Genetics, 2001, Vol. 10, No. 14 1441-1448
© 2001 Oxford University Press
SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein
1Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, 2CREST, Japan Science and Technology Corporation, Tokyo, Japan, 3Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, 2–6 Musashidai, Fuchu, Tokyo 183-8526, Japan, 4Department of Neurology, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan, 5Laboratory of Molecular and Cellular Pathology, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan, 6Department of Neurology, Teine Keijinkai Hospital, Sapporo, Japan, 7Third Department of Internal Medicine, School of Medicine, Shinshu University, 3-3-1 Asahi, Matsumoto 390-8621, Japan and 8Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan
Received March 29, 2001; Revised and Accepted May 4, 2001.
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ABSTRACT |
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Genetic etiologies of at least 20% of autosomal dominant cerebellar ataxias (ADCAs) have yet to be clarified. We identified a novel spinocerebellar ataxia (SCA) form in four Japanese pedigrees which is caused by an abnormal CAG expansion in the TATA-binding protein (TBP) gene, a general transcription initiation factor. Consequently, it has been added to the group of polyglutamine diseases. This abnormal expansion of glutamine tracts in TBP bears 47–55 repeats, whereas the normal repeat number ranges from 29 to 42. Immunocytochemical examination of a postmortem brain which carried 48 CAG repeats detected neuronal intranuclear inclusion bodies that stained with anti-ubiquitin antibody, anti-TBP antibody and with the 1C2 antibody that recognizes specifically expanded pathological polyglutamine tracts. We therefore propose that this new disease be called SCA17 (TBP disease).
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODS REFERENCES |
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Autosomal dominant cerebellar ataxias (ADCAs) make up a complex group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord (1,2). Presently they are classified according to molecular criteria, but the genetic etiologies of at least 20% of the ADCAs have yet to be determined (3). Interestingly, six of the eight gene-proven spinocerebellar ataxias (SCAs): dentato-rubral pallidoluysian atrophy (DRPLA), SCA1, SCA2, SCA3/ Machado–Joseph disease (MJD), SCA6 and SCA7 have been shown to be caused by an unstable CAG trinucleotide expansion mutation coding for polyglutamine tracts in the responsible genes (4). These findings strongly suggest that expansion of the polyglutamine tract is a major pathogenic mechanism for dominant ataxias. By screening for expanded polyglutamine tracts by western blotting analysis with a monoclonal 1C2 antibody, we recently identified a new dominant ataxia caused by the expansion of polyglutamine tracts in the TATA-binding protein (TBP), a general transcription initiation factor. This locus was registered as SCA17 with the approval of the Genome Nomenclature Committee in HUGO (http://www.gene.ucl.ac.uk/nomenclature/). Despite intensive investigation over several years, the genetic pathways and molecular mechanisms that underlie the neuronal degeneration in this group of diseases remain unknown. Recent findings show that in the mouse and fly models transcriptional dysregulation may have importance in cell dysfunction and eventual cell death (5–10). Our findings provide necessary information for clarifying the pathogenesis of polyglutamine diseases.
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RESULTS |
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1C2 antibody immunoscreening and gene identification
We first conducted 1C2 antibody immunoscreening to identify the expanded polyglutamine tract in lymphoblastoid cell lines from 22 probands, for whom expansions of the eight known CAG repeats associated with neurodegenerative diseases [Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA), DRPLA, SCA1, SCA2, SCA3, SCA6, SCA7] had already been excluded by PCR analysis. Mouse monoclonal 1C2 antibody specifically recognizes proteins of largely expanded polyglutamine tracts, particularly those in pathological ranges (greater than 40 glutamines) (11). Using the method described by Stevanin et al. (12) but with modifications, we identified a new polyglutamine protein of
49 kDa in one proband (Fig. 1). Its molecular weight differs from that of any of the known polyglutamine proteins, strongly indicative that this 49 kDa band is a product of a new gene encoding a polyglutamine tract. Given the similarity of its apparent molecular weight to that of the TBP, we speculated that this 49 kDa protein might be mutant TBP, which is supported by the fact that the monoclonal 1C2 antibody was originally raised against TBP (11). Using the primer pairs flanking the CAG/CAA repeat of the TBP gene, we found that both the proband and his affected sibling had the same repeat expansions (Fig. 2A). We therefore determined the CAG/CAA repeat numbers of the TBP genes of the two affected siblings and their mother in pedigree A (Fig. 3A). The CAG/CAA repeat number for TBP in the healthy mother was 37/39, whereas the numbers in the affected siblings were heterozygous, 37/55 and 39/55 (Fig. 3D and Table 1). The identity of the 49 kDa band was confirmed by western blot analysis of protein extracts from the proband’s lymphoblasts using the monoclonal anti-TBP antibody which recognizes an epitope within N-terminal amino acid residues 1–20 of TBP. It clearly shows that his lymphoblasts (Fig. 2B, lane 2; pedigree A, III-1) expressed an equal amount of abnormally large TBP (49 kDa, upper band) as compared with the wild-type TBP (lower band). The intensities of the wild-type TBP bands in the western blots differ in Figure 1, lane 6 and Figure 2B, lane 2. This is probably due to differences in the reactivities of the 1C2 and anti-TBP antibodies.
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x 174/HaeIII). HC, healthy control; DC, disease control. (B) Total protein lysates of lymphoblasts from the proband’s mother (lane 1) and the proband (lane 2) of pedigree A were immunoblotted with anti-TBP antibody (1TBP18; QED Bioscience). Only the proband has an abnormally large TBP. Because no lymphoblast cell line had been established, the proband’s sister’s (pedigree A, III-2) lymphoblasts were not available.
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PCR screening of expanded CAG/CAA repeat in the TBP gene
In pedigree A, the proband’s father showed dysarthria at the age of 26 and ataxic gait at the age of 34. He became bed-ridden at the age of 35 and died of pneumonia at the age of 37. The disease phenotype in pedigree A, including the two affected siblings, is an autosomal dominantly inherited young-onset cerebellar ataxia and progressing dementia with the later addition of a pyramidal and an extrapyramidal sign, e.g. parkinsonism or trunkal dystonia. This suggests that expansion of the CAG repeats of the TBP gene is associated with a new form of dominant SCA. To investigate this possibility, we screened 316 disease probands whose clinical phenotypes included hereditary spinocerebellar degeneration, sporadic spinocerebellar degeneration, multiple system atrophy, dementia of unknown etiology, chorea and spastic paraplegia. In all these cases, diseases in which the CAG expansions could be attributed to one of the previously identified genes were excluded. The number of CAG/CAA repeats in the TBP gene ranged from 29 to 42 (including one chromosome of 42 repeats) in 116 healthy control chromosomes (Fig. 3B, gray bars). The CAG repeat of the TBP gene has been intensively analyzed (13,14). In a large population study, alleles corresponding to a range of 25–42 glutamine residues were detected, the most common alleles encoding stretches of 32–39 glutamines. A gln42 allele was found only once in 2003 chromosomes representing several different ethnic backgrounds (15). We therefore concluded that a TBP gene having a CAG/CAA number in excess of 43 is pathological. Our 316 disease cases provided three new probands (Fig. 3A, pedigrees B, C, D) whose CAG/CAA repeat number ranged from 47 to 48 (Fig. 3B, black bars; Table 1). Therefore, 43–46 CAG/CAA repeats might be intermediate alleles.
The disease phenotype associated with CAG/CAA expansion in the TBP gene is complex and appears to be transmitted in a manner that defies easy categorization. In pedigrees A and B, the phenotype is transmitted autosomal dominantly, whereas in pedigree C, it seems to occur autosomal recessively. In addition, it seems to occur sporadically in pedigree D. We therefore investigated the nucleotide sequence of the CAG/CAA repeat of the TBP loci of the family members in all the pedigrees to clarify the inheritance pattern of the expanded CAG repeat in the TBP gene. Both siblings (III-1 and III-2) in pedigree A have a heterozygous pattern of gln55 expansion expression at this site (Fig. 3D and Table 1). Their healthy mother (pedigree A, II-9) has gln37/gln39 alleles. These findings indicate that the normal alleles of the proband and his sister were probably maternal transmissions, and the expanded gln55 alleles were paternal ones. Although it was not possible to study their father’s DNA, both the proband’s father and grandfather had a history of spinocerebellar degeneration. In pedigree B, the expanded gln47 allele of the proband was transmitted to both her daughters (III-1 and III-2). At the time of our study, the younger daughter of the 29-year-old had a history of general convulsion, and epilepsy was diagnosed based on her abnormal EEGs. In contrast, the elder daughter at the age of 33 does not yet show any symptom of neurological deficit. We speculate that she may be asymptomatic due to her young age, because our clinical observations show that this disease can have its onset as late as age 48. We could not obtain any clinical information on the proband’s parents (II-1, II-8) in pedigree C, but all three manifesting siblings (III-3, III-5 and III-6) expressed abnormal gln48 alleles heterozygously, whereas the healthy siblings had only normal alleles. In pedigree D, the proband (III-8) has gln32/gln47 alleles, whereas her healthy father (II-5) and brother (III-7) have only normal alleles. No examination of the proband’s mother (II-3) could be made because she had died of breast cancer at the age of 43.
We also found two CAA/CAG expansion patterns by nucleotide sequencing of the TBP gene. One pattern is intragenomic partial duplication, as observed in patients III-1 and III-2 in pedigree A. The other, which is most frequently seen in this disease, is the simple (CAG)y expansion in lesion IV of the TBP gene (Fig. 4D).
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Clinical features of SCA17 (TBP disease)
Age at onset ranged from 19 to 48 years, mean age 33.2 years (n = 6, Table 1). There was a strong inverse correlation (R = –0.88) between age at onset and the number of CAG repeats in the TBP gene (Fig. 3C) inspite of the narrow range of expanded alleles (47–55 repeats) and difficulty in determining the exact age of the first sign of ataxia, bradykinesia or dementia in this disorder. Most individuals presented in the third decade with gait ataxia and dementia, progressing over several decades to include bradykinesia, dysmetria, dysdiadokokinesis, hyper-reflexia and paucity of movement. The first symptom (e.g. ataxia, dementia or parkinsonism) varied with the patient. Parkinsonism in these cases mainly showed bradykinesia, gait disturbance (accelerated gait and marche á petits pas) and postural reflex disturbance (retropulsion), tremor and muscle rigidity being less prominent. The appearance of epilepsy varied, showing first as a neurological symptom in patient III-2 in pedigree B, but appearing in the late stage in patients III-6 in pedigree C and III-8 in pedigree D. No abnormal eye movements were present in any patient. MRI or CT findings for all the patients indicated diffuse cortical and cerebellar atrophy (Fig. 4). Initial clinical diagnoses varied: dementia-related atypical Holme’s type spinocerebellar degeneration (pedigree A), DRPLA-like spinocerebellar degeneration (pedigree B), atypical HD (pedigree C) and atypical parkinsonism with progressive dementia (pedigree D).
Immunocytochemical study of postmortem brain tissues
We conducted an immunocytochemical examination of postmortem brain tissues from a patient (pedigree C, III-5) who had expanded polyglutamine repeats (48) of his TBP. A conventional neuropathological examination revealed shrinkage and moderate loss of small neurons with gliosis in the caudate nucleus and putamen. Large neurons were relatively preserved. Similar but moderate changes were detected in the thalamus, frontal cortex and temporal cortex. Moderate Purkinje cell loss and an increase of Bergmann glia were seen in the cerebellum. Torpedoes were occasionally encountered.
Immunocytochemical analysis performed with anti-ubiquitin (Fig. 5B and H) and anti-TBP (Fig. 5D and K) antibodies showed neuronal intranuclear inclusion bodies (NIIs). In addition, most, if not all, neuronal nuclei were diffusely stained with 1C2-Ab (Fig. 5C), whereas none were stained in the healthy control brains (Fig. 5E and F). Except for SCA2 (16,17) and SCA6 (18), in which abnormal inclusions are present in the cytoplasm, NIIs may provide a marker of disease process in many polyglutamine diseases (19,20). The presence of NIIs in the brain of the patient who had expanded polyglutamine repeats (48) further confirmed that this disorder should be categorized as a polyglutamine disease.
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DISCUSSION |
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TBP is an important general transcription initiation factor (15,21) and the DNA-binding subunit of RNA polymerase II transcription factor D (TFIID), the multi-subunit complex crucial for the expression of most genes (22,23). The long polyglutamine domain is located in the N-terminus of TBP which regulates the DNA-binding activity of the C-terminus of the protein (24,25). Imbert et al. (26) first suggested the possibility of a role for this N-terminal expanded CAG repeat of TBP in certain late-onset neurologic disorders. Since then, this gene has been investigated intensively as a candidate for psychiatric disorders (13,26,27).
We show here for the first time that CAG expansion in the TBP gene does cause a neurological disorder inherited in an autosomal dominant manner that is classified as a novel polyglutamine disease. Several lines of evidence support our conclusion that polyglutamine expansion in the TBP is pathogenic and the causative agent of a novel type of disease phenotype. (i) The disease phenotype completely co-segregates with the genotype of the abnormally expanded CAG/CAA repeat and arises from a heterozygously expanded TBP allele in all the patients in the four pedigrees we have examined. (ii) The clinical features of young-onset ataxia, dementia and parkinsonism are very common. (iii) The disease phenotype detected in this study shares a feature (very common ) with a case of de novo TBP mutation (14), whereas the clinical feature appears to be more complex and severer in a sporadic case (63 CAG repeats). (iv) Except for one previously reported case (14), there has been no report of a CAG expansion of more than 43 repeats. (v) We found a strong negative correlation between age at onset and the number of polyglutamine repeats (R2 value = 0.78), a correlation frequently found in other polyglutamine disorders. (vi) NII bodies were present in a diseased brain which carried 48 CAG repeats. We found no evidence, however, indicative of the instability of the CAG repeat in germline transmission, a characteristic feature of polyglutamine diseases.
The precise molecular mechanism that operates in the present disease is not clear. Nuclear localization of the protein with the expanded polyglutamine tract, however, has been indicated as crucial to polyglutamine disease pathogenesis (8,28–30). Of the eight known causative genes of polyglutamine diseases, TBP is the third gene, along with the androgen receptor and CACNL1A4 (the genes responsible for SBMA and SCA6, respectively), whose function is well understood. Taking into account the fact that TBP is abundant in the nucleus and is essential for gene expression, its participation in polyglutamine diseases favors a molecular pathogenesis for these diseases. When bound to the TATA box, TBP has a saddle-like shape with its concave face contacting the DNA and its convex one interacting with the other TFIID subunits, the TBP-associated factors (TAFs) (23). The tertiary structural change caused by polyglutamine expansion in TBP may lead to an aberrant affinity for TAFs, culminating in altered gene expression and cell death. Indeed, human TAFp130 that binds to the polyglutamine domain of the DRPLA protein is lengthdependent (9). Lin et al. (8) reported that in transgenic mice the expression of several neuronal genes involved in calcium homeostasis and signal transduction are down-regulated very soon after the expression of mutant ataxin-1 protein (8). Polyglutamine-expanded huntingtin, but not normal huntingtin, interacts both in vivo and in vitro with the transcriptional repressor N-CoR (nuclear receptor corepressor), and N-CoR and at least one of its corepressors, Sin3, are localized ectopically in the cytoplasm of brain sections from HD patients (31). In contrast, co-localization of transcription factors such as CREB-binding protein (CBP) (10,32), TBP itself (33,34), TAFII130 (9) and Sin3a (31), is reported to be recruited into the NIIs. All these findings provide strong evidence that in polyglutamine diseases major transcriptional changes occur in the nucleus.
Further study of what takes place in the dying neuron’s nucleus in this disease should provide important information for unraveling the molecular pathogenesis of neuronal cell degeneration as well as for the development of future therapeutic interventions.
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MATERIALS AND METHODS |
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Patients
We interviewed families and collected blood samples after obtaining the fully informed consent of the patients and their families.
Western blot analysis of lymphoblasts
This procedure is described in detail elsewhere (12,35). Briefly, lymphoblast cells (5 x 106) were washed in phosphate-buffered saline (PBS) and resuspended in 2 ml of Tris-buffered saline (TBS, 20 mM Tris–HCl, 150 mM sodium chloride pH 7.5) with 1 mM EDTA and the protease inhibitors (Complete, Boehringer Mannheim, Germany). The cells were then homogenized in an ultrasonicator and centrifuged at 10 000 g at 4°C for 30 min. The supernatant was collected, and the protein concentration determined with a BCA protein assay kit (Pierce, Rockford, IL). Samples were stored at –80 C° until they were used. Protein samples (50 µg/lane) were separated by SDS–PAGE in a 0.1% SDS/5–20% gradient polyacrylamide gel then transferred to Immobilon membranes (Millipore, MA). The membranes were blocked with 1% bovine serum albumin and 4% dry milk in TBST buffer (TBS with 0.05% Tween 20) for 1 h at room temperature, after which they were incubated overnight at 4°C in 3% dry milk/TBST with the 1C2 Ab (1:2000; Chemicon, Temecula, CA) and given three 10 min washes in TBST. The filters then were incubated in 3% dry milk/TBST with HRP-conjugated secondary anti-mouse Ig Ab (1:5000). Finally, the reaction was made visible with an enhanced chemiluminescence (ECL) western blotting kit (Amersham Pharmacia Biotech, UK) according to the manufacturer’s protocol. Mouse monoclonal anti-TBP antibody (1TBP18; QED Bioscience, CA) at 1:2000 dilution was used for the TBP immunoblotting.
PCR and GeneScan analysis of the TBP gene
The PCR of the TBP gene was done with the forward primer TBP-F, 5'-CCTTATGGCACTGGACTGAC-3', and reverse primer TBP-R, 5'-GTTCCCTGTGTTGCCTGCTG-3'. The patient’s genomic DNA was amplified in a 25 µl reaction mixture containing DNA template (60–150 ng), dNTP (200 µM each), 10 pmol of each primer, 2.5 µl of 10x PCR buffer and AmpliTaq Gold polymerase (5 U; Perkin Elmer, Foster City, CA). Optimal PCR conditions were initial denaturation at 95°C for 12 min, followed by 40 cycles of 20 s at 95°C, 1 min at 60°C, 1 min at 72°C, and final extension at 72°C for 10 min. All the PCR reactions were done in a thermal cycler (iCycler; Bio-Rad, Hercules, CA). PCR products were separated by electrophoresis through 3.5% agarose and made visible by CYBER Green I (Molecular Probes, Eugene, OR) staining. For the GeneScan analysis, forward primer TBP-F was replaced by FAM-labeled primers (TBP-FAM). The GS500 TAMRA-labeled size standard (Perkin Elmer) and PCR products were run simultaneously in the same lanes. The CAG repeat size was determined with an ABI 377XL DNA sequencer and GeneScan version 3.1 software.
Direct sequencing of CAG/CAA polymorphism in the TBP gene
Amplified DNA fragments bearing the TBP gene (nucleotides 338–563; NM_003194, gi: 4507378) were subcloned into pGEM-T Easy vector (Promega, Madison, WI). DNA sequences of the polymorphic site in the TBP gene were verified in 10 individual clones from each genomic DNA template. Homozygotic or heterozygotic CAG alleles of the TBP gene were also authenticated on the basis of the CAG/CAA numbers obtained from the GeneScan analysis.
Immunocytochemical analysis of postmortem brain tissue
We obtained postmortem brain tissue (pedigree C, III-5) from the brain bank (NH No. A-157) at the Tokyo Metropolitan Institute for Neuroscience. Formalin-fixed, paraffin-embedded sections, 4 mm thick, were prepared from the caudate nucleus, putamen and frontal cortex of the patient and the control subjects. Two pre-treatment protocols were used. Sections were autoclaved and treated with 99% formic acid for 5 min at room temperature or microwaved in 10 mM citrate buffer (pH 6.0), then treated with 1% periodic acid for 15 min, after which they were immunostained by the ABC method (Vector, Burlingame, CA) with mouse monoclonal 1C2 (1:1000–16 000, Chemicon), rabbit polyclonal (sc204, 1:20 000, Santa Cruz; Santa Cruz, CA), mouse monoclonal (1TBP18, 1:20000, QED Bioscience; San Diego, CA), anti-TBP antibody or rabbit polyclonal antibody against ubiquitin (1:1000; Dakopatts, Carpinteria, CA). Diaminobenzidine was used as the chromogen. Double immunofluorescence analysis was performed by incubating de-paraffinized sections with a mixture of 1C2 monoclonal antibody (1:1000) and anti-ubiquitin (1:500) or anti-TBP (1:250) rabbit polyclonal antibody. Anti-mouse IgG coupled with Rhodamine red (1:200, Jackson ImmunoRes, West Grove, PA) was used to make the 1C2 epitope visible. Anti-rabbit Ig G coupled with horseradish peroxidase (1:1000, Pierce, Rockford, IL) reacted with biotinylated tyramide which enabled the other epitope to be made visible with FITC conjugated with streptavidin (1:200, Vector). After being mounted with Vectashield (Vector), the sections were observed under a fluorescent microscope equipped with a laser confocal system (TCS-SP, Leica, Heidelberg, Germany).
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ACKNOWLEDGEMENTS |
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We are grateful to Dr N. Arai (Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience) who provided the autopsied brain sample for DNA analysis. We also thank N. Koikeda, N. Tsuji, M. Arai and K. Matsuba for their technical assistance. This work was supported in part by a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant no. 112210051).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +81 3 3815 5411; Fax: +81 3 5805 5845; Email: koichiro-tky@umin.ac.jp
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REFERENCES |
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 A. McCampbell, A. A. Taye, L. Whitty, E. Penney, J. S. Steffan, and K. H. Fischbeck Histone deacetylase inhibitors reduce polyglutamine toxicity PNAS, December 6, 2001; (2001) 261400698. [Abstract] [Full Text] [PDF]
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E. Martin-Aparicio, A. Yamamoto, F. Hernandez, R. Hen, J. Avila, and J. J. Lucas Proteasomal-Dependent Aggregate Reversal and Absence of Cell Death in a Conditional Mouse Model of Huntington's Disease J. Neurosci., November 15, 2001; 21(22): 8772 - 8781. [Abstract] [Full Text] [PDF]
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A. Matilla, C. Gorbea, D. D. Einum, J. Townsend, A. Michalik, C. van Broeckhoven, C. C. Jensen, K. J. Murphy, L. J. Ptacek, and Y.-H. Fu Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex Hum. Mol. Genet., November 1, 2001; 10(24): 2821 - 2831. [Abstract] [Full Text] [PDF]
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R. J. Sinke, E. F. Ippel, C. M. Diepstraten, F. A. Beemer, J. H. J. Wokke, B. J. van Hilten, N. V. A. M. Knoers, H. K. P. van Amstel, and H. P. H. Kremer Clinical and Molecular Correlations in Spinocerebellar Ataxia Type 6: A Study of 24 Dutch Families Arch Neurol, November 1, 2001; 58(11): 1839 - 1844. [Abstract] [Full Text] [PDF]
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C. Zander, J. Takahashi, K. H. El Hachimi, H. Fujigasaki, V. Albanese, A. S. Lebre, G. Stevanin, C. Duyckaerts, and A. Brice Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3 Hum. Mol. Genet., October 1, 2001; 10(22): 2569 - 2579. [Abstract] [Full Text] [PDF]
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A. McCampbell, A. A. Taye, L. Whitty, E. Penney, J. S. Steffan, and K. H. Fischbeck Histone deacetylase inhibitors reduce polyglutamine toxicity PNAS, December 18, 2001; 98(26): 15179 - 15184. [Abstract] [Full Text] [PDF]
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